The aim of the present study is to profile differentially expressed protein markers between left-sided colon cancer (LSCC) and right-sided colon cancer (RSCC). Fresh tumor tissue samples from LSCC (n = 7) and RSCC (n = 7) groups were analyzed by two-dimensional electrophoresis coupled with MALDI-TOF-MS, followed by Western blotting. In 50 paraffin embedded samples from each group, levels of four differentially expressed proteins (identified by proteomics analysis) were measured by tissue microarray with immunohistochemistry staining to compare the different protein markers between LSCC and RSCC. Sixteen proteins were found to be differentially expressed between LSCC and RSCC. Ten proteins including HSP-60 and PDIA1 were identified to be highly expressed in LSCC (P < 0.01 or P < 0.05), while the expression of six proteins including EEF1D and HSP-27 were higher in RSCC (P < 0.01 or P < 0.05). Virtually all of the indentified proteins were involved in cellular energy metabolism, protein folding/unfolding, and/or oxidative stress. Human colon tumors at various locations have different proteomic biomarkers. Differentially expressed proteins associated with energy metabolism, protein folding/unfolding and oxidative stress contribute to different tumorigenesis, tumor progression, and prognosis between left-and right-sided colon cancer. (Cancer Sci 2013; 104: 135-141) C olon cancer is one of the most common causes of cancerrelated deaths worldwide. In the United States alone, an estimated 101 340 new cases and 49 380 deaths due to colon cancer were recorded in 2011.(1) The molecular mechanisms of carcinogenesis and colon cancer progression are therefore of major clinical importance.With the splenic flexure as the boundary, the colon is anatomically divided into left and right sides. The left-sided colon includes the splenic flexure, descending and sigmoid colons, while the right side includes the ileocecal junction, ascending and transverse colons. Existing evidence indicates that leftsided colon cancer (LSCC) differs importantly from right-sided colon cancer (RSCC) in terms of epidemiology, risk factors, clinical manifestations, and metastatic characteristics. The prevalence of colon cancer location (i.e. left or right) changes with age in both sexes. Older patients are more likely to have RSCC, which grow larger than left-sided lesions.(2) Also while males have a higher prevalence of tumors, women tend to present with right-sided tumor development.(3) Konopke et al. (4) reported that most liver metastases of the right hemicolon were located in the right lobe, while left colonic carcinomas tended to spread homogeneously to both liver lobes. Right-sided colon cancer (RSCC) also shows fewer adenomatous remnants than LSCC.